The Fredrickson classification system for hyperlipidemia uses plasma appearance, total cholesterol and triglyceride values to characterize subjects with one of five types of hyperlipidemia. The five types are I, II, III, IV and V. Type II is further subdivided in to type IIa and type IIb, whereby both types have elevated total cholesterol and LDL-C, type IIb also presents with elevated triglycerides.
Reports have estimated the prevalence of type IIb hyperlipidemia (type IIb) in the population at about 10%. Type IIb is characterized by elevation in LDL-C, triglyceride, and apolipoprotein B levels, and an increased level of very low density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL), and small dense LDL.
Type IIb hyperlipidemia encompasses acquired combined hyperlipidemia and familial combined hyperlipidemia (FCHL). FCHL is a genetic condition, occurring in approximately 0.3-2% of the population, although estimates as high as 5.7% of the population have been reported. Individuals with type IIb hyperlipidemia have an increased rate of cardiovascular disease and those individual with FCHL have a high incidence of premature coronary artery disease. In addition, type IIb patients have a higher incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis hepatitis (NASH) than do patients without type IIa, a form of fatty liver, that develops due to hepatic triglyceride overproduction and accumulation. NAFLD, NASH or fatty liver can lead to metabolic complications including elevation of liver enzymes, fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Liver failure is life-threatening and therefore there is an urgent need to develop therapies to delay development, prevent formation or reverse the condition of a fatty liver.
Current treatment options for type IIb hyperlipidemia are limited. While statin are very effective at lowering LDL-C, in general they are not very effective at lowering triglyceride levels. Some statins at high dose levels, for example atorvastatin at 80 mg, do significantly lower triglyceride levels. However, high dose statin therapy can cause muscle pain (myalgia) and is often not well tolerated by patients. In addition, high dose statin therapy carries with it an increased risk for serious muscle toxicity such as rhabdomyolysis.
Further, because certain statins are metabolized by cytochrome P450 enzymes that also mediate metabolism of other drugs, the use of higher doses of statins may be contraindicated for use with certain drugs. The finding, disclosed in the present application, that a combination of gemcabene and low to moderate dose of a statin cause surprising synergy in the lowering of triglycerides (TG) may allow the use of lower doses of statin and therefore a better safety profile.
Treatments for type IIb hyperlipidemia focus on lowering LDL-C levels and triglyceride levels. Treatment typically includes administering a combination of a cholesterol lowering agent, such as a statin, and a triglyceride lowering agent, such as a fibrate, niacin or fish oil. However, the commonly used triglyceride lowering agents may not be convenient or may not be well tolerated, for example, fibrates are associated with myalgia and an increased risk of muscle toxicity, fish oil needs to be taken multiple times daily, and niacin causes flushing particularly when administered in combination with statins. Certain fibrates use or activate the cytochrome P450 3A4 isoform as part of their catabolic process as do some statins, and administration of these drugs in combination can increase the risk of myalgia and muscle damage. Physicians may avoid combining a statin with fibrates because of concern over the higher risk of muscle damage with the combination.
Nonalcoholic fatty liver disease (NAFLD) is increasingly common around the world, especially in western nations. In the United States, it is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. Nonalcoholic fatty liver disease is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. As the name implies, the main characteristic of nonalcoholic fatty liver disease is too much fat stored in liver cells. It is normal for the liver to contain some fat. However, if more than 5%-10% percent of the liver's weight is fat, the condition is called a fatty liver (steatosis). NAFLD is strongly associated with features of metabolic syndrome, including obesity, insulin resistance, type-2 diabetes mellitus, and dyslipidemia; it is considered the hepatic manifestation of this syndrome.
Pediatric NAFLD is currently the primary form of liver disease among children. Studies have demonstrated that abdominal obesity and insulin resistance are thought to be key contributors to the development of NAFLD. Because obesity is becoming an increasingly common problem worldwide the prevalence of NAFLD has been increasing concurrently. The only treatment shown to be truly effective in pediatric NAFLD is weight loss.
The more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH). NASH causes the liver to swell and become damaged. NASH tends to develop in people who are overweight or obese, or have diabetes, high cholesterol or high triglycerides or inflammatory conditions. NASH, a potentially serious form of the disease, is marked by hepatocyte ballooning and liver inflammation, which may progress to scarring and irreversible damage. This damage is similar to the damage caused by heavy alcohol use. Macro and microscopically, NASH is characterized by lobular and/or portal inflammation, varying degrees of fibrosis, hepatocyte death and pathological angiogenesis. At its most severe, NASH can progress to cirrhosis, hepatocellular carcinoma and liver failure. Currently NAFLD and NASH are being treated e.g., by diet, treatment of insulin resistance or vitamin administration, such as vitamins E or D. Unfortunately there are currently no drugs approved for the treatment of NAFLD or NASH.
NAFLD Activity score (NAS) can be calculated according to the criteria of Kleiner (Kleiner D E. et al., Hepatology, 2005; 41:1313). NAS scores 0-2 are not considered diagnostic for NASH, NAS scores of 3-4 are considered either not diagnostic, borderline or positive for NASH, while NAS scores of 5-8 are largely considered diagnostic for NASH. A treatment effect for NASH includes the regression, stabilization or a reduction in the rate of disease progression. Sequential liver biopsies from a patient that may have NASH can be used to assess the change in the NAS score and used as an indication of the change in the disease state. A score that increases suggests progression, an unchanged score suggests stabilization, while a decreased score suggests regression of NASH. In a controlled clinical trial, the difference in NAS scores between the placebo and the test article treatment group, assessed usually over a duration of 6 months to two years, can be indicative of a treatment effect, even if both groups are progressing. A defined point spread is usually required by a regulatory authority to demonstrate a meaningful change in NASH.
Fibrinogen (factor I) is a mammalian glycoprotein that plays a role in the in the formation of blood clots. Fibrinogen is converted to fibrin by thrombin during blood clot formation. Fibrinogen is synthesized in liver hepatocytes. A variety of diseases are associated with elevated levels of fibrinogen and include but are not limited to NASH, microvascular disease, peripheral vascular disease, peripheral artery disease, critical limb ischemia in peripheral arterial occlusive disease, new-onset coronary atherosclerosis, decreased survival in cancer, such as in breast cancer, renal cell carcinoma, prostate cancer patients. Increased fibrinogen levels are also associated with a negative sepsis outcome, diabetes, metabolic syndrome, and subacute thyroiditis, plasma triglyceride, obesity, ultrasound intra-abdominal fat, diastolic blood pressure, insulin resistance, LDL-cholesterol and cigarette smoking. Severity of obstructive sleep apnea is also associated with elevated plasma fibrinogen in otherwise healthy patients.
Fibrinogen therefore may be a prognostic indicator or blood marker for many disease and may also serve to effect the onset and progression of the disease state. There is a medical need to reduce fibrinogen in a subject with elevated levels.
Because the treatment options are limited for patient having type IIb hyperlipidemia and because the current treatments may increase the risk of serious side effects or may not be well tolerated, there is a need for additional treatments that are safe and effective for treating patients suffering from type IIb hyperlipidemia. Additionally, the current treatments for NAFLD and NASH are limited, there is a need for more treatment options that are safe and effective for treating patients suffering from NAFLD and NASH.